# Investigating the lipid transport properties of VPS13C at membrane contact sites in relation to Parkinsons Disease pathogenesis

> **NIH NIH F31** · YALE UNIVERSITY · 2020 · $30,300

## Abstract

Project Summary/Abstract
Parkinson's Disease (PD) is the most common neurodegenerative movement disorder, affecting about 1% of
the population over 65 years-old. At least a large percentage of PD cases have some genetic component and
many genes have been identified that are either causative of familial forms of the disease or enhance disease
risk. While PD does not have a monogenic origin in most patients, studies of genes whose mutations are
sufficient to cause disease will help reveal pathogenic mechanisms. The vacuolar protein sorting 13C
(VPS13C) locus was initially linked to PD through genome-wide association studies (GWAS), and more
recently loss-of-function mutations in the gene encoding VPS13C were shown to cause early-onset, autosomal
recessive PD. VPS13C, a 422 kDa protein, is one of four mammalian paralogues (VPS13A, B, C and D) whose
mutations result in either neurodegenerative or neurodevelopmental diseases. Studies of the single Vps13
protein in yeast have shown that it localizes at membrane contact sites between either the mitochondria and
vacuole (the yeast lysosome), or between the vacuole and the ER, and have suggested that it may play a role
in lipid transfer. Little is known about the function of VPS13 family members in mammals. Studies of VPS13C
have suggested various localizations (lipid droplets (LDs), lysosomes and mitochondria). Additionally, VPS13C
knock-down in fibroblastic cells was reported to cause mitochondrial defects and exacerbate PINK1/Parkin-
dependent mitophagy. The overall goal of my proposal is to investigate the physiological role of VPS13C and
to explore the mechanism by which VPS13C loss-of-function contributes to PD pathogenesis. My preliminary
data, based on the expression of tagged VPS13C, suggests its localization at contact sites between the
endoplasmic reticulum (ER) and either late-endosomes/lysosomes (LE/LYS) or lipid droplets (LDs), but not at
contacts involving mitochondria. They also support a role of VPS13C in lipid transfer at organelle contacts. I
plan to corroborate these data by tagging the protein at the endogenous locus in cultured cells (including
human iPS-derived neuronal cells) to study its localization/dynamics when expressed at endogenous levels. To
test the hypothesis that VPS13C mediates lipid transfer, I will perform lipidomic analysis of cells and tissues
harboring loss-of-function mutations in the VPS13C gene, and in subcellular fractions derived from this
material (endosomes/lysosomes, ER, and mitochondria) to detect alterations in the lipid composition.
Furthermore, I will use microscopy, biochemical, and functional approaches to investigate defects in
endosomal sorting and lysosome function, as well as any potential downstream mitochondrial defects that may
underlie neurodegeneration. Finally, I will investigate the consequences of VPS13C knockout in mice on
structural features of the CNS (the nigrostriatal pathway in particular), as well as on survival and motor function.
...

## Key facts

- **NIH application ID:** 9841732
- **Project number:** 5F31NS110229-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** William Franklin Hancock-Cerutti
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $30,300
- **Award type:** 5
- **Project period:** 2018-12-01 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841732

## Citation

> US National Institutes of Health, RePORTER application 9841732, Investigating the lipid transport properties of VPS13C at membrane contact sites in relation to Parkinsons Disease pathogenesis (5F31NS110229-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9841732. Licensed CC0.

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